Porcine to Human Heart Transplantation: Is Clinical Application Now Appropriate?

Cardiac xenotransplantation (CXTx) is a promising solution to the chronic shortage of donor hearts. Recent advancements in immune suppression have greatly improved the survival of heterotopic CXTx, now extended beyond 2 years, and life-supporting kidney XTx. Advances in donor genetic modification (B4GALNT2 and CMAH mutations) with proven Gal-deficient donors expressing human complement regulatory protein(s) have also accelerated, reducing donor pig organ antigenicity. These advances can now be combined and tested in life-supporting orthotopic preclinical studies in nonhuman primates and immunologically appropriate models confirming their efficacy and safety for a clinical CXTx program. Preclinical studies should also allow for organ rejection to develop xenospecific assays and therapies to reverse rejection. The complexity of future clinical CXTx presents a substantial and unique set of regulatory challenges which must be addressed to avoid delay; however, dependent on these prospective life-supporting preclinical studies in NHPs, it appears that the scientific path forward is well defined and the era of clinical CXTx is approaching

An acquired Gerbode defect from the left ventricle to the coronary sinus following mitral valve replacement

We report the management of an acquired Gerbode defect, from the left ventricle to the coronary sinus, following mechanical mitral valve replacement. Following a failed percutaneous closure, surgical patch closure of the defect was performed

Individualized surgical strategies for left ventricular outflow tract obstruction in hypertrophic cardiomyopathy

OBJECTIVES: Surgical strategies to treat drug refractory left ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy include septal myectomy (SM) and, less frequently, mitral valve (MV) repair or replacement. The primary aim of this study was to report the surgical technique and management outcomes in a consecutive group of patients with variable phenotypes of hypertrophic cardiomyopathy in a broad national specialist practice. METHODS: A total of 203 consecutive patients, 132 men (mean age 48.6 ± 14.6 years) underwent surgery for the management of LVOTO. Surgical approaches included SM (n = 159), SM with MV repair (n = 25), SM with MV replacement (n = 9) and MV replacement alone (n = 10). Specific surgical approaches were performed based on the underlying mechanism of obstruction. Eleven (5.4%) patients had previous alcohol septal ablation for the management of LVOTO. Concomitant non-mitral cardiac procedures were carried out in 22 (10.8%) patients. RESULTS: Operative survival rate was 99.0% with 2 deaths within 30 days. The mean bypass time was 92.9 ± 47.8 min, with a mean length of hospital stay of 10.5 ± 7.8 days. Surgical complications included 3 ventricular septal defects requiring repair (1.5%), 1 Gerbode defect surgically repaired, 2 aortic valve repairs (1.0%), 2 transient ischaemic attacks (1.0%) and 4 strokes (2.0%). Thirty-nine (19.2%) patients had perioperative new-onset atrial fibrillation and 8 (3.9%) patients had unexpected atrioventricular block requiring a permanent pacemaker. Mean resting left ventricular outflow tract gradient improved from 70.6 ± 40.3 mmHg preoperatively to 11.0 ± 10.5 mmHg at 1 year postoperatively (P < 0.001). Mean New York Heart Association class improved from 2.6 ± 0.5 preoperatively to 1.6 ± 0.6 at 1 year after the procedure. CONCLUSIONS: In variable phenotypes of LVOTO in hypertrophic cardiomyopathy, an individualized surgical approach provided effective reductions in left ventricular outflow tract gradients and good symptomatic relief with acceptable mortality and morbidity

Methods of cardiac preservation alter the function of the endothelium in porcine coronary arteries

This study was undertaken to determine whether clinical methods for preservation and storage of hearts explanted for transplantation affect the responsiveness of coronary arteries to vasoactive agents. Porcine hearts were perfused with crystalloid or blood cardioplegic solution. Rings of coronary arteries were suspended in organ chambers for measurement of isometric force (1) immediately after perfusion and (2) after 5 hours' storage of the hearts at 4° C in the same cardioplegic solution (n = 6 in each group). The maximal contraction of the smooth muscle to potassium chloride, 40 mmol/L, was reduced significantly after perfusion with crystalloid cardioplegic solution (10.8 ± 1.2 gm) compared with blood cardioplegic solution (17.3 ± 0.8 gm) and nonperfused coronary arteries (control group 16.9 ± 1.8 gm). The sensitivity of the arteries with endothelium to the contractile effects of prostaglandin F(2α) increased after perfusion with crystalloid cardioplegic solution (ED50, [-log mol/L] 5.8 ± 0.04) compared with blood cardioplegic solution (5.3 ± 0.02) and the control group (5.7 ± 0.03). In addition, relaxations to the calcium ionophore A23187, bradykinin, and the α2-agonist BHT-920, which depend on the presence of endothelial cells, were significantly reduced after perfusion with crystalloid compared with blood cardioplegic solution or the control group. The responsiveness of the endothelium and smooth muscle after 5 hours' cold storage was unaltered in the blood cardioplegia group, whereas storage resulted in functional recovery in the crystalloid cardioplegia group, with the result that all groups were comparable. These data suggest an immediate and reversible change in vascular function with crystalloid cardioplegia, which was not apparent with blood cardioplegia.link_to_subscribed_fulltex

Right and left ventricular remodeling after orthotopic single lung transplantation for end-stage emphysema

BACKGROUND: Orthotopic single lung transplantation (LTX) is now an established treatment modality for patients with end-stage emphysema. LTX has been shown to cause unloading of the right ventricle with improvement in right ventricular (RV) structure and function both immediately and up to weeks after surgery, mostly in patients with severe pulmonary hypertension and decreased RV function. Long-term effects of lung transplantation on both RV and left ventricular (LV) anatomy and function, however, are not well known. METHODS: Seventeen patients undergoing LTX for end-stage emphysema and preserved RV function underwent serial electron beam computed tomography RV and LV function studies before, 3 months after, 1 year after, and 2 years after transplantation. Right-sided heart catheterization was performed before transplantation and at 1 and 2 years follow-up. RESULTS: RV end systolic volume decreased significantly (-15.5%), and RV ejection fraction increased significantly (+16%) in the first 3 months after LTX. This change was paralleled by a decrease in pulmonary pressure and vascular resistance, indicating a permanent RV unloading. This improvement was maintained up to 2 years after LTX. LV end-diastolic volume (+25%), LV stroke volume (+29%), and LV muscle mass (+28%) increased significantly in the first 3 months after LTX. This remodeling was maintained during the 2-year follow-up. CONCLUSIONS: Significant changes in cardiac anatomy and function occur shortly after LTX, most likely as a consequence of adaptation to a new hemodynamic state in patients with well preserved RV function before LTX. Furthermore, these acute changes persist for at least 2 years after LTX

A plea for precaution with public health : the xenotransplantation example.

In this paper we argue that while individual private interests such as autonomy and the need for a medical procedure or treatment are important in the provision and delivery of health care and the utilization of biotechnologies, these concepts need to be balanced with other interests such that in certain situations they do not take priority. We use as an example a particular developing biotechnology, xenotransplantation, to suggest that interest in the health of the public is such that this biotechnology should not be permitted to move to the clinical trial stage because of the particular risk of harm it poses to the potential xeno-recipient, their close contacts and the wider population. This is despite the interest of those in need of a transplant in allowing such clinical trials to proceed. We derive support for our position from John Stuart Mill's harm principle

Histopathologic insights into the mechanism of anti‐non‐Gal antibody‐mediated pig cardiac xenograft rejection

The histopathology of cardiac xenograft rejection has evolved over the last 20 yr with the development of new modalities for limiting antibody-mediated injury, advancing regimens for immune suppression, and an ever-widening variety of new donor genetics. These new technologies have helped us progress from what was once an overwhelming anti-Gal-mediated hyperacute rejection to a more protracted anti-Gal-mediated vascular rejection to what is now a more complex manifestation of non-Gal humoral rejection and coagulation dysregulation. This review summarizes the changing histopathology of Gal- and non-Gal-mediated cardiac xenograft rejection and discusses the contributions of immune-mediated injury, species-specific immune-independent factors, transplant and therapeutic procedures, and donor genetics to the overall mechanism(s) of cardiac xenograft rejection